Dihydromyricetin (DHM) is a natural flavonoid showing several health promoting effects such as protective activity during severe alcohol intoxication. The mechanism underlying the effects of DHM on alcohol metabolism is virtually unknown. The present paper is focused on clarifying the role of DHM in the liver alcohol elimination at its molecular level. First, impact of DHM on alcohol dehydrogenase (ADH) activity in vitro and the enzyme induction in vivo was examined. Neither the ADH activity nor the enzyme expression were influenced by DHM. Next, the effect of DHM during alcohol intoxication were studied on primary hepatocytes isolated from EtOH-premedicated and untreated rats. The viability of cells exposed to alcohol, estimated based on the released enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), was slightly affected by DHM. Although the expected hepatoprotective effect of DHM was not fully achieved, DHM (in a concentration manner) proved to reduce the level of ROS/RNS in hepatocytes. However, no change in the rate of alcohol metabolism in vivo was found when rats were administered with a single or repeated dose of ethanol supplemented with DHM. In conclusion, the proposed positive effect of DHM during alcohol intoxication has not been proven. Moreover, there is no effect of DHM on the alcohol metabolism. The "hoped-for" DHM hepatoprotective activity can be attributed to the reduction of ROS/RNS levels in cells.

• MeSH
• alkoholdehydrogenasa metabolismus   MeSH
• antioxidancia farmakologie   MeSH
• cytochrom P-450 CYP2E1 metabolismus   MeSH
• ethanol metabolismus   MeSH
• flavonoly farmakologie   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• játra účinky léků   metabolismus   MeSH
• kultivované buňky MeSH
• metabolická inaktivace MeSH
• nitrosativní stres účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• reaktivní formy dusíku metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkoholdehydrogenasa MeSH
• antioxidancia MeSH
• cytochrom P-450 CYP2E1 MeSH
• dihydromyricetin MeSH Prohlížeč
• ethanol MeSH
• flavonoly MeSH
• reaktivní formy dusíku MeSH
• reaktivní formy kyslíku MeSH

BACKGROUND: A statistical pipeline was developed and used for determining candidate genes and candidate gene coexpression networks involved in 2 alcohol (i.e., ethanol [EtOH]) metabolism phenotypes, namely alcohol clearance and acetate area under the curve in a recombinant inbred (RI) (HXB/BXH) rat panel. The approach was also used to provide an indication of how EtOH metabolism can impact the normal function of the identified networks. METHODS: RNA was extracted from alcohol-naïve liver tissue of 30 strains of HXB/BXH RI rats. The reconstructed transcripts were quantitated, and data were used to construct gene coexpression modules and networks. A separate group of rats, comprising the same 30 strains, were injected with EtOH (2 g/kg) for measurement of blood EtOH and acetate levels. These data were used for quantitative trait loci (QTL) analysis of the rate of EtOH disappearance and circulating acetate levels. The analysis pipeline required calculation of the module eigengene values, the correction of these values with EtOH metabolism rates and acetate levels across the rat strains, and the determination of the eigengene QTLs. For a module to be considered a candidate for determining phenotype, the module eigengene values had to have significant correlation with the strain phenotypic values and the module eigengene QTLs had to overlap the phenotypic QTLs. RESULTS: Of the 658 transcript coexpression modules generated from liver RNA sequencing data, a single module satisfied all criteria for being a candidate for determining the alcohol clearance trait. This module contained 2 alcohol dehydrogenase genes, including the gene whose product was previously shown to be responsible for the majority of alcohol elimination in the rat. This module was also the only module identified as a candidate for influencing circulating acetate levels. This module was also linked to the process of generation and utilization of retinoic acid as related to the autonomous immune response. CONCLUSIONS: We propose that our analytical pipeline can successfully identify genetic regions and transcripts which predispose a particular phenotype and our analysis provides functional context for coexpression module components.

• Klíčová slova
• Alcohol Metabolism, HXB/BXH Recombinant Inbred Rat Panel, Liver, Quantitative Trait Locus Mapping, RNA Sequencing, Weighted Gene Coexpression Network Analysis,
• MeSH
• ethanol aplikace a dávkování   metabolismus   MeSH
• játra účinky léků   metabolismus   MeSH
• krysa rodu Rattus MeSH
• metabolická clearance účinky léků   fyziologie   MeSH
• multifaktoriální dědičnost účinky léků   fyziologie   MeSH
• pití alkoholu genetika   metabolismus   MeSH
• potkani inbrední BN MeSH
• potkani inbrední SHR MeSH
• potkani transgenní MeSH
• strojové učení bez učitele * MeSH
• systémová biologie metody   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• ethanol MeSH